(1). Field of the Invention
The present invention generally relates to mutants of Mycobacterium tuberculosis. More particularly, the invention is directed to M. tuberculosis mutants that affect host cell apoptosis.
(2). Description of the Related Art
References
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Mycobacterium tuberculosis, the etiological agent of tuberculosis, is responsible for more deaths each year than any other single pathogen (Corbett et al., 2003). The emergence of drug resistant strains of M. tuberculosis and HIV co-infection has contributed to the worsening impact of this disease. The pathogen exhibits extraordinary capacity to subvert and resist bactericidal responses of its infected host. M. tuberculosis virulence has been associated with its initial survival within macrophages by evading the host response in many different ways. The tubercle bacilli reside in endocytic vacuoles (Armstrong and Hart, 1975; Clemens and Horwitz, 1995), which fail to fuse to lysosomes due to M. tuberculosis mediated retention of a host protein TACO on the membrane of these vacuoles (Gatfield and Pieters, 2000). Similarly, M. tuberculosis can downregulate the expression of MHC-II (Noss et al., 2001) and costimulatory molecules (Stenger et al., 1998; Wadee et al., 1995), modulate the cytokine environment in its vicinity (VanHeyningen et al., 1997) and inhibit apoptosis of the host cell (Keane et al., 1997). Although M. tuberculosis evades many host responses to maintain itself in a habitable environment, the bacterial effectors mediating such effects need to be delineated. On invading the host cell, a capsule-like structure is formed outside the membrane and the cell wall of the tubercle bacilli (Daffe and Etienne, 1999), and this interface contains important surface proteins involved in the pathogenesis and immune responses to TB, The secreted and cell envelope associated proteins, located at the interface between the mycobacterium and its eukaryotic host mediate host-pathogen interactions. Therefore, such proteins are candidate virulence factors and warrants further study (Finlay and Falkow, 1997).
The exported and secreted proteins of M. tuberculosis have been proposed to play a role in virulence and indeed contribute to the immune responses to TB (Abou-Zeid et al., 1988; Johansen et al., 1996; Nagai et al., 1991; Zhang et al., 1992). Research on several bacterial pathogens has revealed that the majority of virulence factors are secreted (Finlay and Falkow, 1997). Studies have also emphasized the importance of the secreted and exported proteins of M. tuberculosis in the generation of a protective immune response. The most striking demonstration of this property comes from experiments in which mice or guinea pigs were immunized with extracellular proteins and significant protective immunity elicited (Andersen, 1994; Hubbard et al., 1992; Pal and Horwitz, 1992; Roberts et al., 1995). Recently, the exported ERP (exported repetitive protein) protein was shown to contribute to the virulence of M. tuberculosis (Berthet et al., 1998). Likewise, superoxide dismutase (SOD), a culture filtrate component was shown to be associated with virulence by interfering with host apoptosis (Edwards et al., 2001). While many secreted proteins have been studied, the study of the cell surface proteins is still lacking due to technological constraints in isolating samples of membrane proteins.
Host cell apoptosis has been implicated in Mycobacterium spp. virulence and protective immunity (e.g., Alemán et al., 2002; Balcewicz-Sablinska et al., 1998; Ciaramella et al., 2000; Duan et al., 2001, 2002; Duarte et al., 1997; Eddine et al., 2005; Grode et al., 2005; Keane et al., 2000; Kornfeld et al., 1999; López et al., 2003; Protales-Pérez et al., 2002; Sly et al., 2003; Spira et al., 2003). However, there is need for more information on Mycobacterium host genes that affect host cell apoptosis. The present invention addresses that need.